Gonadoblastoma locus and the TSPY gene on the human Y chromosome

Abstract

The gonadoblastoma (GBY) locus is the only oncogenic locus on the human Y chromosome. It is postulated to serve a normal function in the testis, but could exert oncogenic effects in dysgenetic gonads of individuals with intersex and/or dysfunctional testicular phenotypes. Recent studies establish the testis-specific protein Y-encoded (TSPY) gene to be the putative gene for GBY. TSPY serves normal functions in male stem germ cell proliferation and differentiation, but is ectopically expressed in early and late stages of gonadoblastomas, testicular carcinoma in situ (the premalignant precursor for all testicular germ cell tumors), seminomas, and selected nonseminomas. Aberrant TSPY expression stimulates protein synthetic activities, accelerates cell proliferation, and promotes tumorigenicity in athymic mice. TSPY binds to type B cyclins, enhances an activated cyclin B-CDK1 kinase activity, and propels a rapid G(2)/M transition in the cell cycle. TSPY also counteracts the normal functions of its X-homologue, TSPX, which also binds to cyclin B and modulates the cyclin B-CDK1 activity to insure a proper G(2)/M transition in the cell cycle. Hence, ectopic expression and actions of the Y-located TSPY gene in incompatible germ cells, such as those in dysgenetic or ovarian environments and dysfunctional testis, disrupt the normal cell cycle regulation and predispose the host cells to tumorigenesis. The contrasting properties of TSPY and TSPX suggest that somatic cancers, such as intracranial germ cell tumors, melanoma, and hepatocellular carcinoma, with detectable TSPY expression could exhibit sexual dimorphisms in the initiation and/or progression of the respective oncogenesis.

Sexual dimorphism in cancer

“…TSPY is another Y-linked gene, coding for a SET/NAP (SET proto-oncogene /nucleosome assembly protein), with a known function in male germ cell differentiation, mitosis, and meiosis 149 . Increased TSPY expression occurs in testicular germ cell tumors 149 , as well as various types of somatic cancer, including melanoma 150 , prostate 151 and liver cancer 152 .…”

“…Increased TSPY expression occurs in testicular germ cell tumors 149 , as well as various types of somatic cancer, including melanoma 150 , prostate 151 and liver cancer 152 . Interestingly, while TSPY appears to exert a pro-oncogenic function, it has a homologue on the X chromosome, TSPX, which can be tumour suppressive 153 and protects from hepatitis B viral infection, a major risk for HCC 154 .…”

The Y chromosome-linked copy number variations and male fertility

“…The TSPY1 belongs to a protein superfamily comprising SET and NAP, which are activating factors of the replication process. Indeed, TSPY1 is abundantly expressed in early stages of tumorigenesis in gonadoblastoma and could be potentially involved in other human cancers (48). Expression analysis in the testis indicates the involvement of the TSPY1 in spermatogenesis as a pro-proliferative factor (48).…”

“…Indeed, TSPY1 is abundantly expressed in early stages of tumorigenesis in gonadoblastoma and could be potentially involved in other human cancers (48). Expression analysis in the testis indicates the involvement of the TSPY1 in spermatogenesis as a pro-proliferative factor (48). In fact, TSPY1 is mainly expressed in gonocytes/ pre-spermatogonia of embryonic testis and in spermatogonia and spermatocytes at meiotic prophase I in adult testis.…”

Sequence Recombination in Exon 1 of the Tspy Gene in Men With Impaired Fertility

“…The TSPY protein binds mitotic and meiotic cyclin B. It can affect mitotic and meiotic divisions and accelerate the G 2 /M transition in the cell cycle 19,23 . In addition, rat TSPY can bind histones in the cytoplasm of spermatids.…”